Background
Nutrient metabolism influences HIV-1 replication, immunity, and chronic inflammation but is difficult to target therapeutically. We hypothesized that regulating metabolism via caloric restriction (CR), a safe, anti-aging modality with anti-inflammatory effects could improve SIV disease outcome in rhesus macaques (RMs).
Methods
Healthy, non-obese, adult male and female RMs (n=6) were experimentally restricted to consume 30% fewer daily calories than ad-libitum (AL) intake. After 3 months of CR, animals were infected with SIVmac239, left untreated for 28 days, and given ART for 11 months while maintaining CR. Animals were compared to age, gender, and weight-matched AL-fed RMs (n=10). Immune phenotypic profiling by flow, plasma SIV load, and -omic classification of soluble proteins/metabolites in plasma were assessed during acute SIV (14 dpi) and 11 months of ART.
Results
CR was safe, well tolerated, and led to modest reduction in weight and fat/lean mass ratio. CR animals exhibited near log fold reductions in acute phase viremia (AUC) when compared to that of the AL-fed cohort (-0.8log, Fig. A). Viremic control in CR was characterized by more robust memory CD8 T cell proliferative response in lymphoid (p=0.008) and gut tissues (p=0.03). At 11 months of ART, CR animals had lower immune cell infiltration (Fig. B) and reduced levels of HLA-DR+ CD4 (p=0.0013) and CD8 (p=0.008) memory T cells in the colon. This was also associated with lower sCD14 (p=0.0002) and several TNF-related proteins (p=0.002). Of the 376 acute SIV metabolites, LASSO regression revealed a set of 3: Spermidine, ADP, and Glucose-1-phosphate (breakdown product of glycogen and galactose stores) that inversely predicted lower plasma SIV AUC. Indeed, ex vivo glycolytic flux and mTORC1 activity was higher in PBMCs (p=0.009) and memory CD8 T cells of CR animals during acute SIV (p=0.03). During ART, LASSO suggested a central role for glutamine metabolism, with 2-oxoglutarate (TCA intermediate promoting gut enterocyte proliferation), and cysteinylglycine (glutathione-derived antioxidant), as predictive markers of colonic reconstitution.
Conclusions
The data highlight that diet, in regulation of caloric content, can have a significant therapeutic impact on SIV disease outcomes. Pharmacologically reducing caloric intake by mimicking satiety with glucagon-like peptide-1 agonists, which are currently taken by 16 million US adults, warrants further investigation in the context of virologic control and residual inflammation in HIV-1.